ClinVar Miner

Submissions for variant NM_000080.4(CHRNE):c.103T>C (p.Tyr35His) (rs144169073)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000413280 SCV000333199 uncertain significance not provided 2015-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000413280 SCV000490469 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing The Y35H pathogenic variant in the CHRNE gene has been previously reported, using alternative nomenclature, in multiple individuals with congenital myasthenia syndrome who harbor an additional variant on their other CHRNE allele (Ealing et al., 2002; Palace et al., 2012; Webster et al., 2014). It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, nor was it observed with any significant frequency in the 1000 Genomes Project. The Y35H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and missense variants in nearby residues (L31P; R40W) have been reported in the Human Gene Mutation Database in association with congenital myasthenia syndrome (Stenson et al., 2014). In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret Y35H as a pathogenic variant.
Athena Diagnostics Inc RCV000413280 SCV000612745 likely pathogenic not provided 2016-10-13 criteria provided, single submitter clinical testing
Invitae RCV000551170 SCV000641235 uncertain significance Myasthenic syndrome, congenital, 4a, slow-channel 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 35 of the CHRNE protein (p.Tyr35His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is present in population databases (rs144169073, ExAC 0.1%). This variant has been reported along with a second variant in individuals affected with congenital myasthenic syndrome (PMID: 12417530, 24295813, 21940170, 17878953). ClinVar contains an entry for this variant (Variation ID: 282036). This variant is also known as p.Tyr15His in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000825313 SCV000966608 uncertain significance not specified 2018-01-10 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Tyr35His variant in CHRNE has been reported in the compound heterozygous state in 6 indiv iduals with congenital myasthenic syndrome, and segregated with disease in two a ffected members of one family (reported as p.Tyr15His; Ealing 2002, Palace 2012, Webster 2014). It has also been identified in 0.1% (146/126616) of European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut; dbSNP rs144169073). In vitro functional studies provide some evidence tha t the p.Tyr35His variant may impact protein function (Ealing 2002). However, the se types of assays may not accurately represent biological function. Computation al prediction tools and conservation analysis also suggest that the variant may impact the protein, though this information is not predictive enough to determin e pathogenicity. In summary, while there is some suspicion for a pathogenic role , the clinical significance of the p.Tyr35His variant is uncertain due to its fr equency in the general population. ACMG/AMP Criteria applied: PM3_Supporting; PS 4_Moderate; PP3; PS3_Supporting; BS1_Supporting.
Baylor Genetics RCV001004609 SCV001163795 pathogenic Congenital myasthenic syndrome 4C criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001125182 SCV001284221 uncertain significance Congenital myasthenic syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001328993 SCV001520272 pathogenic Myasthenic syndrome, congenital, 4b, fast-channel 2019-11-26 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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